dbSNP rs76114496: HERC1:p.Thr2696Thr (chr15-63669656-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003922.4(HERC1):c.8088A>G(p.Thr2696Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00871 in 1,613,902 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 87 hom. )

Consequence

HERC1
NM_003922.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0260

Publications

1 publications found

Variant links:

Genes affected

HERC1 (HGNC:4867): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 1) This gen encodes a member of the HERC protein family. This protein stimulates guanine nucleotide exchange on ARF1 and Rab proteins. This protein may be involved in membrane transport processes. [provided by RefSeq, Mar 2012]

HERC1 Gene-Disease associations (from GenCC):

macrocephaly, dysmorphic facies, and psychomotor retardation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
megalencephaly-severe kyphoscoliosis-overgrowth syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HERC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 15-63669656-T-C is Benign according to our data. Variant chr15-63669656-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.026 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00608 (926/152350) while in subpopulation NFE AF = 0.0105 (711/68036). AF 95% confidence interval is 0.00981. There are 7 homozygotes in GnomAd4. There are 440 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003922.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	NM_003922.4	MANE Select	c.8088A>G	p.Thr2696Thr	synonymous	Exon 40 of 78	NP_003913.3	Q15751

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC1	ENST00000443617.7	TSL:1 MANE Select	c.8088A>G	p.Thr2696Thr	synonymous	Exon 40 of 78	ENSP00000390158.2	Q15751

Frequencies

GnomAD3 genomes

AF:

0.00608

AC:

926

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00519

AC:

1293

AN:

249094

AF XY:

0.00499

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00959

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00899

AC:

13135

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

6328

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.00271

AC:

121

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00398

AC:

104

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000209

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00176

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0111

AC:

12345

AN:

1111740

Other (OTH)

AF:

0.00684

AC:

413

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

595

1190

1785

2380

2975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

484

968

1452

1936

2420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00608

AC:

926

AN:

152350

Hom.:

Cov.:

AF XY:

0.00591

AC XY:

440

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41576

American (AMR)

AF:

0.00719

AC:

110

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

711

AN:

68036

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00771

Hom.:

Bravo

AF:

0.00597

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.6

(source)

DANN

Benign

0.61

PhyloP100

0.026

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over